Ingenol mebutate (ingenol-3-angelate), derived from the sap of the plant Euphorbia peplus, is a highly bioactive diterpene ester with cytotoxic and immune-stimulatory activity.1-3 Numerous
studies have evaluated the biological effects of ingenol mebutate in cancer-related indications.4 Ingenol mebutate has been FDA-approved for the treatment of actinic keratosis. Actinic keratosis is confined to the epidermis, caused by UV-induced DNA-damage to the skin following prolonged sun exposure, and can develop into potentially life-threatening squamous cell carcinoma.
5,6 Due to this risk of developing severe forms of non-melanoma
skin cancer from untreated actinic keratoses, treatment of actinic keratosis is now considered an important step towards the prevention of skin cancer forms with greater morbidity.7
Cell death induced by ingenol mebutate is observed at high micromolar concentrations and has been reported to bear
characteristics of necrotic cell death presenting with unchanged or dilated nuclei and swollen mitochondria.2 Only a subset of cancer cell lines is particularly sensitive to ingenol mebutate, probably mediated by activation of the PKC-delta isoform.8,9 Currently, the clinical efficacy of ingenol mebutate in actinic keratosis is attributed to a combination of direct cytotoxic and PKC-dependent accessory effects, sometimes called a dual mechanism of action.10
We sought to better define the molecular basis of ingenol mebutate-mediated cell death. Our results suggest that the
cytotoxic effects of ingenol mebutate in cancer cells and normal keratinocytes are caused by different molecular mechanisms, are subsequent to changes in mitochondrial structure, and
depend on the cellular differentiation state.
Treatment And Analysis Of Full Thickness Skin Equivalents
Ingenol mebutate 0.05% (1.15 mM) gel was applied to human full thickness (epidermis and dermis) skin equivalents EpidermFT
(MatTek Corporation, Ashland, MA) in a volume of 10 μl
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